Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism

• 成果类型: Article
• 署名作者: Macleod, Kenneth; Coquelin, Kevin-Sebastien; Huertas, Leticia; Simeons, Frederick R. C.; Riley, Jennifer; Casado, Patricia; Guijarro, Laura; Casanueva, Ruth; Frame, Laura; Pinto, Erika G.; Ferguson, Liam; Duncan, Christina; Mutter, Nicole; Shishikura, Yoko; Henderson, Colin J.; Cebrian, David; Wolf, C. Roland; Read, Kevin D.
• 署名单位: University of Dundee; University of Dundee; GlaxoSmithKline; Glaxosmithkline United Kingdom
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10502
• DOI: 10.1073/pnas.2315069121
• 发表日期: 2024-02-13
• 关键词: pregnane-x-receptor; constitutive androstane receptor; human-liver; therapeutic-efficacy; leishmania-donovani; trypanosoma-cruzi; transgenic mouse; in-vitro; efavirenz; pharmacokinetics

摘要

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse- specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily (8HUM) can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis, Leishmania donovani, and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse- specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery. Significance Mouse models of disease are widely used to test the efficacy of new compounds during drug discovery and development. However, largely due to species differences in the cytochrome P450 system, mice have a higher capacity for drug metabolism than humans and produce a different spectrum of metabolites. Here, we show that use of mice humanized for these drug- metabolizing enzymes can circumvent these impediments, allowing refocus of compound optimization toward human pharmacokinetics and pharmacodynamics, and improving the alignment of the data generated with clinical observations. The implication of our study is that wild- type mice should be replaced by humanized mice in early and preclinical drug development.